Zoledronate in Treating Osteopenia or Osteoporosis in Postmenopausal Women Receiving Letrozole for Stage I, Stage II, or Stage IIIA Primary Breast Cancer

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00436917
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 60
• Locations: 2
• Arm: 1
• Actual Duration (Months): 121.3
• Patients Per Site: 30
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Zoledronate may reduce bone loss in patients receiving letrozole for breast cancer.

PURPOSE: This clinical trial is studying how well zoledronate works in treating osteopenia or osteoporosis in postmenopausal women receiving letrozole for stage I, stage II, or stage IIIA primary breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Osteoporosis	Drug: zoledronic acid; Procedure: Letrozole as adjuvant therapy	N/A

Detailed Description

OBJECTIVES:

Primary

• Assess changes in total lumbar spine bone mineral density (BMD) from baseline to 12 months in postmenopausal women treated with zoledronate for osteopenia or osteoporosis and letrozole for hormone receptor-positive, stage I-IIIA primary breast cancer.

Secondary

• Determine changes in total lumbar spine BMD from baseline to 2, 3, 4, and 5 years in these patients.

• Determine changes in femoral neck BMD from baseline to 1, 2, 3, 4, and 5 years in these patients.

• Determine time to disease progression in these patients.

OUTLINE: This is an open-label, multicenter study.

• Adjuvant aromatase inhibitor therapy: Patients receive oral letrozole daily for up to 5 years in the absence of disease progression or unacceptable toxicity.

• Osteoporosis management: Patients receive zoledronate IV over 15 minutes on day 1. Patients also receive oral elemental calcium twice daily and oral vitamin D daily for 6 months. Treatment repeats every 6 months for up to 5 years in the absence of disease progression or unacceptable toxicity.

Patients undergo total lumbar spine and hip (femoral neck) bone density testing by dual energy x-ray absorptiometry (DXA) at baseline and annually for 5 years.

After completion of study therapy, patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women With Primary Breast Cancer Undergoing Adjuvant Aromatase Inhibitor (Letrozole) Therapy
• Actual Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: May 9, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: zoledronic acid 4 mg 15 minutes IV infusion. If creatinine clearance is ≤ 60, dosage should be adjusted as follows:CrCl 50-60: 3.5 mg; CrCl 40-49: 3.3 mg; CrCl 30-39: 3.0 mg.	Drug: zoledronic acid; zoledronic acid; Other Names: Zometa® ; Procedure: Letrozole as adjuvant therapy; standard care; Other Names: Femara®

Outcome Measures

Primary Outcome Measures

1. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) [Baseline and 1 year]

   Change: BMD values at twelve months post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

Secondary Outcome Measures

1. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry [Baseline and 2 year]

   Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

2. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry [Baseline and 3 year]

   Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

3. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry [Baseline and 4 year]

   Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

4. Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry [Baseline and 5 year]

   Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

5. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry [Baseline and 1 year]

   Change: BMD values at year 1 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

6. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry [Baseline and 2 year]

   Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

7. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry [Baseline and 3 year]

   Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

8. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry [Baseline and 4 year]

   Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

9. Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry [Baseline and 5 year]

   Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.

10. Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications [5 years]

    Adverse events were assessed per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1=Mild, Grade 2=Moderate.

11. Time to Disease Progression [Up to 5 years]

    Time to disease progression was defined as the time from date of randomization to the documentation of disease progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of localized breast cancer

• Stage I-IIIA disease

• Adequately treated breast cancer

• No clinical or radiological evidence of recurrent or metastatic disease

• Baseline total lumbar spine or femoral neck bone mineral density T-score < -2.0 standard deviation (e.g., a patient with a T score of -2.1 is eligible)

• Hormone-receptor status:

• Estrogen receptor and/or progesterone receptor-positive breast cancer

PATIENT CHARACTERISTICS:

• Female

• Postmenopausal, defined by 1 of the following criteria:

• Age > 55 years with cessation of menses

• Age ≤ 55 years with spontaneous cessation of menses for > 1 year

• Age ≤ 55 years with spontaneous cessation of menses for ≤ 1 year, but amenorrheic (e.g., spontaneous or secondary to hysterectomy), AND has postmenopausal estradiol levels

• Bilateral oophorectomy

• ECOG performance status 0-2

• Life expectancy ≥ 5 years

• WBC ≥ 3,000/mm³ OR granulocyte count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)

• AST ≤ 3 times ULN

• Creatinine < 2.0 mg/dL

• Creatinine clearance ≥ 45 mL/min

• No hypercalcemia (i.e., calcium level > 1 mg/dL above ULN) OR hypocalcemia (i.e., calcium level > 0.5 mg/dL below lower limit of normal) within the past 6 months

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

• No other nonmalignant systemic diseases, including any of the following:

• Uncontrolled infection

• Uncontrolled diabetes mellitus

• Uncontrolled thyroid dysfunction

• Disease affecting bone metabolism (hyperparathyroidism, hypercortisolism, Paget's disease, osteogenesis imperfecta)

• Malabsorption syndrome

• No uncontrolled seizure disorders associated with falls

• No known hypersensitivity to zoledronate or other bisphosphonates, letrozole, calcium, or vitamin D

• No concurrent active dental problems, including any of the following:

• Infection of the teeth or jawbone (maxillary or mandibular)

• Dental or fixture trauma

• Prior or current diagnosis of osteonecrosis of the jaw

• Exposed bone in the mouth

• Slow healing after dental procedures

• No contraindication to spine dual energy x-ray absorptiometry (DXA) as defined by any of the following:

• History of surgery at the lumbosacral spine, with or without implantable devices

• Scoliosis with a Cobb angle > 15 degrees at the lumbar spine

• Immobility, hyperostosis, or sclerotic changes at the lumbar spine, or evidence of sclerotic abdominal aorta sufficient to interfere with DXA scan

• Disease of the spine that would preclude the proper acquisition of a lumbar spine DXA

• No condition that would preclude study follow-up or compliance

• No psychiatric illness that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

• More than 3 weeks since prior and no other concurrent oral bisphosphonates

• No prior intravenous bisphosphonates

• No prior aromatase inhibitor therapy

• More than 6 months since prior anabolic steroids or growth hormone

• More than 2 weeks since prior and no concurrent inhibitor of osteoclastic bone resorption (e.g., calcitonin, mithramycin, or gallium nitrate)

• More than 30 days since prior systemic investigational drug and/or device

• More than 7 days since prior topical investigational drug

• More than 6 weeks since prior and no concurrent dental or jaw surgery (e.g., extraction, implants)

• Concurrent short-term corticosteroid therapy allowed

• No concurrent sodium fluoride, parathyroid hormone, or tibolone

• No other concurrent investigational drug or device

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Stephanie Hines, MD, Mayo Clinic
• Principal Investigator: Charles L. Loprinzi, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00436917
• Other Study ID Numbers: MC05C8; P30CA015083; MC05C8; 2330-05
• First Posted: Feb 19, 2007
• Last Update Posted: Sep 11, 2019
• Last Verified: Apr 1, 2016

• Keywords provided by Mayo Clinic: stage I breast cancer; stage II breast cancer; stage IIIA breast cancer; osteoporosis
• Additional relevant MeSH terms: Breast Neoplasms; Osteoporosis; Bone Diseases, Metabolic; Zoledronic Acid; Letrozole

Study Results

Participant Flow

Recruitment Details	Sixty participants were recruited between June 2006 and July 2007 at 6 individual sites participating in the Mayo Clinic Cancer Research Consortium (MCCRC).

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Period Title: Overall Study
STARTED	53
COMPLETED	32
NOT COMPLETED	21

Baseline Characteristics

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Overall Participants	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.9 (10.0)
Sex: Female, Male (Count of Participants)
Female	53 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 3.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	51 96.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Prior tamoxifen (participants) [Number]
Yes	24 45.3%
No	29 54.7%
Duration of tamoxifen use (participants) [Number]
Missing	29 54.7%
<=2 years	4 7.5%
>2 years	20 37.7%
Time since tamoxifen ended (participants) [Number]
Missing	29 54.7%
<1 year	20 37.7%
>=1 year	4 7.5%
Prior chemotherapy (participants) [Number]
Yes	20 37.7%
No	33 62.3%
Previous fracture by history or X-ray (participants) [Number]
Yes	7 13.2%
No	46 86.8%
Bone Mineral Density Measurement in Lumbar Spine (g/cm2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/cm2]	0.86 (0.12)

Outcome Measures

1. Primary Outcome

Title	Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD)
Description	Change: BMD values at twelve months post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

The primary analysis is performed on data where participants had the same baseline and 1 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	30
Mean (95% Confidence Interval) [Percentage of the baseline value]	2.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid
	Comments	A sample of 60 participants was estimated to provide percentage statistics accuracy to within 13% with 95% confidence.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Kruskal-Wallis
	Comments

2. Secondary Outcome

Title	Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 2 Post Study Entry
Description	Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 2 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 2 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	27
Mean (95% Confidence Interval) [Percentage of the baseline value]	4.94

3. Secondary Outcome

Title	Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 3 Post Study Entry
Description	Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 3 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 3 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	22
Mean (95% Confidence Interval) [Percentage of the baseline value]	6.20

4. Secondary Outcome

Title	Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 4 Post Study Entry
Description	Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 4 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 4 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	13
Mean (95% Confidence Interval) [Percentage of the baseline value]	6.99

5. Secondary Outcome

Title	Average Intra-patient Change in Total Lumbar Spine (L1 to L4) Bone Mineral Density (BMD) at Year 5 Post Study Entry
Description	Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 5 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 5 year BMD Lumbar Spine measurement location (L1-L4, L2-L4 or 'other Lumbar Spine')

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	11
Mean (95% Confidence Interval) [Percentage of the baseline value]	11.71

6. Secondary Outcome

Title	Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 1 Post Study Entry
Description	Change: BMD values at year 1 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 1 year BMD Femoral Neck measurement location (Left femoral, right femoral)

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	32
Mean (95% Confidence Interval) [Percentage of the baseline value]	5.66

7. Secondary Outcome

Title	Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 2 Post Study Entry
Description	Change: BMD values at year 2 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 2 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 2 year BMD Femoral Neck measurement location (Left femoral, right femoral)

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	29
Mean (95% Confidence Interval) [Percentage of the baseline value]	10.47

8. Secondary Outcome

Title	Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 3 Post Study Entry
Description	Change: BMD values at year 3 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 3 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 3 year BMD Femoral Neck measurement location (Left femoral, right femoral)

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	28
Mean (95% Confidence Interval) [Percentage of the baseline value]	8.44

9. Secondary Outcome

Title	Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 4 Post Study Entry
Description	Change: BMD values at year 4 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 4 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 4 year BMD Femoral Neck measurement location (Left femoral, right femoral)

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	14
Mean (95% Confidence Interval) [Percentage of the baseline value]	4.49

10. Secondary Outcome

Title	Average Intra-patient Change in Femoral Neck Bone Mineral Density (BMD) at Year 5 Post Study Entry
Description	Change: BMD values at year 5 post study entry minus BMD values at baseline, expressed as a percentage of the baseline value.
Time Frame	Baseline and 5 year

Outcome Measure Data

Analysis Population Description

Analysis was performed on data where participants had the same baseline and 5 year BMD Femoral Neck measurement location (Left femoral, right femoral)

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	14
Mean (95% Confidence Interval) [Percentage of the baseline value]	4.54

11. Secondary Outcome

Title	Maximum-Grade Toxicity Incidence at Least Possibly Related to Study Medications
Description	Adverse events were assessed per NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1=Mild, Grade 2=Moderate.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	53
Grade 1 Arthralgia	7 13.2%
Grade 2 Arthralgia	4 7.5%
Grade 3 Arthralgia	1 1.9%
Grade 1 Creatinine Increase	7 13.2%
Grade 2 Creatinite increase	2 3.8%
Grade 2 Desquamating Rash	1 1.9%
Grade 2 Headache	1 1.9%
Grade 2 Hot flashes	3 5.7%
Grade 1 Nausea	2 3.8%
Grade 3 Pain in extremity	1 1.9%
Grade 1 Fever	2 3.8%
Grade 1 Vomiting	1 1.9%
Grade 1 Musculoskeletal disorder	1 1.9%
Grade 2 Urogenital disorder	1 1.9%

12. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression was defined as the time from date of randomization to the documentation of disease progression.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

None of the participants had disease progression.

Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
Measure Participants	0

Adverse Events

Time Frame	Adverse event data were collected every 6 months on treatment up to 5 years.
Adverse Event Reporting Description	One participant was excluded from adverse event reporting due to the adverse event data was not available beyond the baseline time point. Adverse event data were collected every 6 months on treatment up to 5 years.
Arm/Group Title	Zoledronic Acid
Arm/Group Description	4 mg intravenously over 15 minutes every 6 months (until disease progression or for 5 years)
All Cause Mortality
	Zoledronic Acid
	Affected / at Risk (%)	# Events
Total	0/52 (0%)
Serious Adverse Events
	Zoledronic Acid
	Affected / at Risk (%)	# Events
Total	1/52 (1.9%)
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder	1/52 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Zoledronic Acid
	Affected / at Risk (%)	# Events
Total	45/52 (86.5%)
Gastrointestinal disorders
Nausea	6/52 (11.5%)	7
Vomiting	2/52 (3.8%)	2
General disorders
Fatigue	1/52 (1.9%)	1
Fever	4/52 (7.7%)	4
Investigations
Creatinine increased	11/52 (21.2%)	31
INR increased	1/52 (1.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	39/52 (75%)	128
Musculoskeletal disorder	2/52 (3.8%)	2
Myalgia	1/52 (1.9%)	1
Pain in extremity	1/52 (1.9%)	1
Nervous system disorders
Headache	1/52 (1.9%)	1
Psychiatric disorders
Depression	1/52 (1.9%)	1
Renal and urinary disorders
Urogenital disorder	1/52 (1.9%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	1/52 (1.9%)	1
Vascular disorders
Hot flashes	3/52 (5.8%)	3
Hypertension	1/52 (1.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.